Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion
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Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. / Klopocki, Eva; Lohan, Silke; Doelken, Sandra C; Stricker, Sigmar; Ockeloen, Charlotte W; Soares Thiele de Aguiar, Renata; Lezirovitz, Karina; Mingroni Netto, Regina Celia; Jamsheer, Aleksander; Shah, Hitesh; Kurth, Ingo; Habenicht, Rolf; Warman, Matthew; Devriendt, Koenraad; Kordass, Ulrike; Hempel, Maja; Rajab, Anna; Mäkitie, Outi; Naveed, Mohammed; Radhakrishna, Uppala; Antonarakis, Stylianos E; Horn, Denise; Mundlos, Stefan.
In: J MED GENET, Vol. 49, No. 2, 02.2012, p. 119-25.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion
AU - Klopocki, Eva
AU - Lohan, Silke
AU - Doelken, Sandra C
AU - Stricker, Sigmar
AU - Ockeloen, Charlotte W
AU - Soares Thiele de Aguiar, Renata
AU - Lezirovitz, Karina
AU - Mingroni Netto, Regina Celia
AU - Jamsheer, Aleksander
AU - Shah, Hitesh
AU - Kurth, Ingo
AU - Habenicht, Rolf
AU - Warman, Matthew
AU - Devriendt, Koenraad
AU - Kordass, Ulrike
AU - Hempel, Maja
AU - Rajab, Anna
AU - Mäkitie, Outi
AU - Naveed, Mohammed
AU - Radhakrishna, Uppala
AU - Antonarakis, Stylianos E
AU - Horn, Denise
AU - Mundlos, Stefan
PY - 2012/2
Y1 - 2012/2
N2 - BACKGROUND: Split-hand/foot malformation (SHFM)-also known as ectrodactyly-is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1-6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved.METHODS: High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments.RESULTS: Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ~11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins.CONCLUSIONS: Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of non-penetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.
AB - BACKGROUND: Split-hand/foot malformation (SHFM)-also known as ectrodactyly-is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1-6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved.METHODS: High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments.RESULTS: Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ~11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins.CONCLUSIONS: Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of non-penetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.
KW - Animals
KW - Basic Helix-Loop-Helix Transcription Factors
KW - Ectromelia
KW - Female
KW - Fingers
KW - Gene Duplication
KW - Gene Knockdown Techniques
KW - Genetic Association Studies
KW - Genotype
KW - Hand Deformities, Congenital
KW - Humans
KW - Inheritance Patterns
KW - Limb Deformities, Congenital
KW - Male
KW - Pedigree
KW - Phenotype
KW - Tibia
KW - Zebrafish
U2 - 10.1136/jmedgenet-2011-100409
DO - 10.1136/jmedgenet-2011-100409
M3 - SCORING: Journal article
C2 - 22147889
VL - 49
SP - 119
EP - 125
JO - J MED GENET
JF - J MED GENET
SN - 0022-2593
IS - 2
ER -